Donepezil hydrochloride, with a chemical name of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidine hydrochloride and chemical structure:
is one of the second generation of cholinesterase (ChE) inhibitors, having a long effect for treating Alzheimer's diseases (AD).
AD is an acquired decline of intelligence accompanied by other cognitive impairments and having hypomnesia as its main symptom. Research in the past thirty years has shown that the progressive degeneration of cholinergic neurons is responsible for hypomnesia, disorientation and change of behavior and personality. This cholinergic theory has been confirmed by a histological study.
Therapeutically, Donepezil can reversibly inhibit hydrolysis of acetylcholine by acetylcholinesterase (AchE) so as to increase acetylcholine at receptors, while Donepezil has a weak effect on acetylcholinesterase in peripheral tissues such as myocardial cells and blood erythrocytes. Donepezil may have other mechanisms, including treatment of peptides, direct effects on neurotransmitter receptors or Ca2+ channels. Donepezil has a good selectivity, high bioavailability, and long half-life, and therefore can be conveniently administrated. Donepezil has an excellent tolerance in patients without hepatotoxicity. Since Donepezil has a significant efficacy on Alzheimer's diseases (AD), the market volume thereof is increasing.
Chinese patent ZL200310106920.3 describes a method for preparing Donepezil.
Japanese patent application with publication number A-64-79151 (corresponding to U.S. Pat. No. 4,895,841, EP296560) discloses some salts of Donepezil, especially Donepezil hydrochloride which has a good efficacy in the prophylaxis and treatment of senile dementia and Alzheimer's disease, and methods for the preparation thereof in industry. Chinese patent with publication number CN1874998A discloses the preparation of Donepezil oxalate and polymorphs thereof.
Senile dementia is one of the common diseases generally occurred in the elder, and is a disease involving central nervous system degeneration with progressive cognitive impairment and memory impairment, of which the main symptoms are memory disorders, decline of calculating ability, visual spatial disorientation, language disorders, decline of understanding and judging ability, mood and behavior disorders. AD patients require long-term treatment, while the Donepezil preparation currently available on the domestic market is a conventional oral preparation, which is very inconvenient for elder patients having difficulty in swallowing.
In comparison with the ordinary tablet, oral liquid, granule, buccal tablet, effervescent tablet, orally disintegrating tablet, lyophilized rapid dissolving tablet and chewable tablet are more convenient and safer for elder patients with dysphagi. Particularly, an orally disintegrating tablet has advantages including that: the tablet could rapidly disintegrate in saliva and rapidly take effect when placed on the tongue without water and chewing; the tablet can be conveniently stored; the preparation process is mature; the production cost is comparable to that of the ordinary tablet; the tablet is very convenient for the elder patients having difficulty in swallowing. In the developed countries, orally disintegrating tablets of Donepezil hydrochloride have become a major preparation.
Some references have reported methods of the preparation of Donepezil hydrochloride, hydrobromide, benzenesulfonate, oxalate, succinate, maleate and fumarate of Donepezil and novel crystal forms thereof. However, neither taste tests of the above-mentioned salts nor non-bitter salts or preparations of Donepezil have been reported to date. Donepezil hydrochloride tastes highly bitter, which cannot be masked by taste-masking agents, which results in that many patients are reluctant to take orally disintegrating tablets of Donepezil hydrochloride.
Therefore, it is highly desirable to develop non-bitter salts of Donepezil, oral liquids, granules, buccal tablets, effervescent tablets, orally disintegrating tablets, lyophilized rapid dissolving tablets and chewable tablets comprising the same.